Pancreatic proteases in the duodenum may exert feedback control of pancreatic exocrine secretion. It is not known if such a system is operative in man. In preliminary studies intraduodenal perfusion of trypsin inhibited phenylalanine-stimulated pancreatic enzyme secretion. We therefore propose to investigate the hypothesis that feedback regulation of pancreatic enzyme secretion by intestinal trypsin occurs in man. Using a gastrointestinal intubation perfusion method we plan to determine the effects of intraduodenal perfusion of trypsin and trypsin inhibitor on basal and phenylalanine-stimulated pancreatic enzyme secretion. The specificity of trypsin as an inhibitor of enzyme secretion will also be examined. In part II of the study we will investigate the hormonal and neural mechanisms responsible for feedback regulation. Cholecystokinin (CCK) is the hormonal stimulus and Pancreatic Polypeptide (PP) the inhibitor of enzyme secretion. Duodenal perfusion of pancreatic enzymes was associated with a fall in plasma CCK and rise in PP levels. Plasma CCK and PP responses to intraduodenal perfusion of phenylalanine with and without the addition of bovine trypsin will be determined. The effects of atropine and naloxone administration on the inhibitory action of tryspin in the duodenum will be examined. The validity of our hypothesis will be further tested in patients with pancreatic insufficiency in whom loss of feedback inhibition can be expected. If our hypothesis is correct we would expect raised CCK and low PP concentrations in the plasma of these patients and acute administration of trypsin in the duodenum should inhibit CCK and stimulate PP release. These studies should increase our comprehension of factors regulating pancreatic secretion and may provide insight into the pathogenesis of and therapeutic approach to chronic pancreatitis.